The vancomycin/ristocetin class of glycopeptide antibiotics are amorphous, amphoteric, strongly laevorotatory compounds of relatively high molecular weight. Structurally, they comprise a heptapeptide aglycone core having phenolic amino acids and, usually, one or more peripheral carbohydrate moieties. See, Williams et al., Topics in Antibiotic Chemistry, Volume 5, pages 119-158. Known members of this class include vancomycin (McCormick et al., U.S. Pat. No. 3,067,099), ristocetin (Philip et al., U.S. Pat. No. 2,990,329), A35512 (Michel et al., U.S. Pat. No. 4,083,964), avoparcin (Kunstmann et al., U.S. Pat. No. 3,338,786 and Debono, U.S. Pat. No. 4,322,343), teicoplanin (Bardone et al., J. Antibiot., Volume 31, page 170, 1978), actaplanin (Raun, U.S. Pat. No. 3,816,618, Boeck et al., U.S. Pat. No. 4,537,715), AAD-216 ("ardacin") (Bowie et al., U.S. Pat. No. 4,548,974), A477 (Raun et al., U.S. Pat. No. 3,928,571), OA7653 (Nishida et al., U.S. Pat. No. 4,378,348), AM 374 (Kunstmann et al., U.S. Pat. No. 3,803,306), K288 (J. Antibiotics, Series A, Volume 14, page 141 (1961), also known as actinoidin), teichomycin (Borghi et al., U.S. Pat. No. 4,542,018, Malabarba et al., The Journal of Antibiotics, Vol. XXXVII, No. 9, p. 988-999, Barna et al., The Journal of Antibiotics, Vol. XXXOII, No. 9, p. 1204-1208), desvancosaminyl and des(vancosaminyl-O-glucosyl) glycopeptides (Nagarajan, U.S. Pat. No. 4,552,701), AAJ-271, (Carr et al. copending application Ser. No. 892,027 now abandoned incorporated herein by reference), A 33512B (U.S. Pat. No. 4,029,769), A 41030 factors a-g (U.S. Pat. No. 770), AAD-609 (Ser. No. 781,422 now U.S. Pat. No. 4,694,069) and CWI-785 (copending applications Ser. Nos. 891,931, now U.S. Pat. No. 4,742,045 and 892,174, now abandoned, incorporated by reference herein).
The glycopeptide antibiotics exhibit antibacterial activity, some having therapeutic uses against gram-positive organisms including methicillin-resistant strains. These strains currently cannot be treated with .beta.-lactam antibiotics, including the newer .beta.-lactamase-resistant cephalosporins. Infections by these pathogens is a serious problem. For example the compounds of this invention may be used to treat staphylococcal endocarditis, osteomyelitis, pneumonia, septicemia, soft tissue infection, staphylococcal enterocolitis and antibiotic-associated pseudomembranous colitis produced by C. difficile. They may also be used for prophylaxis for hip and heart surgery, prophylaxis against bacterial endocarditis and S. aureus infections in hemodialysis patients.
Many glycopeptides have also been demonstrated to increase animal feed utilization efficiency and, therefore, to be useful to promote animal growth, to improve milk production in ruminants and to treat and to prevent ketosis in ruminants. For example, Reynolds et al., British Pat. No. 2137087A, disclose the use of avoparcin to improve milk production; Raun et al., U.S. Pat. No. 3,928,571 disclose the use of actaplanin, avoparcin (A477), vancomycin and ristocetin to promote growth and to prevent and to treat ketosis; Hamill et al., U.S. Pat. No. 3,952,095, disclose the use of actaplanin to promote qrowth; and Ingle et al., U.S. Pat. No. 4,206,203 disclose use of avoparcin to prevent and to treat ketosis.
New improved antibiotics are continually in demand, particularly for the treatment of human diseases. Increased potency, expanded spectrum of bacterial inhibition, increased in vivo efficacy, and improved pharmaceutical properties, such as greater oral absorption, higher blood or tissue concentrations, longer in vivo half life, and more advantageous rate or route of excretion and rate or pattern of metabolism are some of the goals for improved antibiotics.
In addition to searching for such new compounds in nature, chemical derivatives of existing compounds are being made. An early approach was hydrolysis to remove one or more carbohydrate moieties, (e.g. Chan et al., U.S. Pat. No. 4,521,335). Another approach described in Debono, U.S. Pat. No. 4,497,802 is to acylate the amine terminus of the glycopeptide nucleus.